Revisiting a Classic Approach to the Aspidosperma Alkaloids:  An Intramolecular Schmidt Reaction Mediated Synthesis of (+)-Aspidospermidine

Abstract

A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization" and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.

Chemistry of Bridged Lactams and Related Heterocycles

“…326 The synthesis of bridged orthoamides provided the first examples of any intramolecular Schmidt reaction affording exclusively bridged products. 331,332,326 …”

General Asymmetric Synthetic Strategy for the α‐Alkylated 2,5,6‐Trisubstituted Pyran of Indanomycin and Related Natural Products

“…The spectral ( 1 H and 13 C NMR) and analytical data for compound 27 were in good agreement with the data reported . Addition of vinylmagnesium bromide (1.5 equiv., THF, –78 °C) to the ketone 27 to afford alcohol 28 (stereochemistry not assigned) in 95 % yield . Finally, rearrangement of the tertiary alcohol was carried out using pyridinium chlorochromate (PCC) in dichloromethane to furnish α,β‐unsaturated aldehyde 7 in 64 % yield with a 95:5 diastereomeric ratio (crude NMR spectra showed 6:1 ratio).…”

Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo­philes

“…157 Thus, during a complete synthesis of the alkaloid (+)-aspidospermidine, the ring in ketocyclopropane 192 was readily opened by an equimolar mixture of trimethylsilyl azide and tetrabutylammonium fluoride to yield azide 193 (Scheme 109). The ease with which nucleophilic ring opening of 192 occurred was explained in terms of the high stability exhibited by the intermediate enolate ion.…”

“…The ease with which nucleophilic ring opening of 192 occurred was explained in terms of the high stability exhibited by the intermediate enolate ion. 157 The reaction between dinitrocyclopropane 31 and sodium azide gave a stable γ-azidodinitropropane salt that only yielded the corresponding dinitroazidopropane 194 upon acidification (Scheme 110). The Lee group devised an approach to optically active β-substituted γ-butyrolactones by nucleophilic ring opening of enantiomerically pure cyclopropane 170.…”